Risk factors and treatment strategies for cholecystitis after metallic stent placement for malignant biliary obstruction: a multicenter retrospective study.

BACKGROUND AND AIMS: Cholecystitis can occur after self-expandable metallic stent (SEMS) placement for malignant biliary obstruction (MBO), but the best treatment option for cholecystitis has not been determined. Here, we aimed to identify the risk factors of cholecystitis after SEMS placement and determine the best treatment option. METHODS: Incidence, treatments, and predictive factors of cholecystitis were retrospectively evaluated in 1084 patients with distal MBO (DMBO) and 353 patients with hilar MBO (HMBO) who underwent SEMS placement at 12 institutions from January 2012 to March 2021. RESULTS: Cholecystitis occurred in 7.5% of patients with DMBO and 5.9% of patients with HMBO. The recurrence rate was significantly lower (P = .043) and the recurrence-free period significantly longer (P = .039) in endoscopic procedures than in percutaneous procedures for cholecystitis treatment. EUS-guided gallbladder drainage (EUS-GBD) was better in terms of technical success, procedure time, and recurrence-free period than endoscopic transpapillary gallbladder drainage. Obstruction across the cystic duct orifice by tumor (P = .015) and by stent (P = .037) were independent risk factors for cholecystitis in DMBO. Cases with multiple SEMS placements (odds ratio [OR], 11; 95% confidence interval [CI], 0.68-190; P = .091) and with gallbladder stones (OR, 2.3; 95% CI ,0.92-5.6; P = .075) had a higher risk for cholecystitis in HMBO. CONCLUSIONS: The incidences of cholecystitis after SEMS placement for DMBO and HMBO were similar. EUS-GBD is the optimal treatment option for patients with cholecystitis after SEMS placement for MBO.

Effectiveness, safety, and factors associated with the clinical success of endoscopic biliary drainage for patients with hepatocellular carcinoma: a retrospective multicenter study.

BACKGROUND: Only a few reports have assessed the effectiveness of endoscopic biliary drainage (EBD) in hepatocellular carcinoma (HCC) patients with obstructive jaundice and liver dysfunction. METHODS: This was a retrospective study based on the clinical databases from the Okayama University Hospital and 10 affiliated hospitals. All patients received EBD for jaundice or liver dysfunction. The indication for EBD was aggravation of jaundice or liver dysfunction with intrahepatic bile duct (IHBD) dilation. The technical and clinical success rate, complications, factors associated with clinical failure, and survival duration were evaluated. RESULTS: A total of 107 patients were enrolled in this study. Technical success was achieved in 105 of 107 patients (98.1%). Clinical success was achieved in 85 of 105 patients (81%). Complications related to endoscopic retrograde cholangiography (ERC) occurred in 3 (2.8%) patients. Child-Pugh class C (odds ratio 3.90, 95% confidence interval [CI] 1.47-10.4, p = 0.0046) was the only factor associated with clinical failure, irrespective of successful drainage. The median survival duration was significantly longer in patients with clinical success than in those without clinical success (5.0 months vs. 0.93 months; hazard ratio [HR] 3.2, 95% CI 1.87-5.37). HCC Stage I/II/III (HR 0.57, CI 0.34-0.95, p = 0.032), absence of portal thrombosis (HR 0.52, CI 0.32-0.85, p = 0.0099), and clinical success (HR 0.39, CI 0.21-0.70, p = 0.0018) were significant factors associated with a long survival. CONCLUSIONS: EBD for obstructive jaundice and liver dysfunction in patients with HCC can be performed safely with a high technical success rate. Clinical success can improve the survival duration, even in patients expected to have a poor prognosis. TRIAL REGISTRATION: Retrospectively registered.

Combination of Diclofenac and Sublingual Nitrates Is Superior to Diclofenac Alone in Preventing Pancreatitis After Endoscopic Retrograde Cholangiopancreatography.

BACKGROUND & AIMS: Acute pancreatitis is a major adverse event of endoscopic retrograde cholangiopancreatography (ERCP). Rectal administration of nonsteroidal anti-inflammatory drugs (NSAIDs) decreases the incidence of post-ERCP pancreatitis (PEP). Little is known about the combined effects of sublingual nitrate and NSAIDs. We performed a randomized trial to assess whether the combination of NSAIDs and sublingual nitrate is more effective than NSAIDs alone in preventing PEP. METHODS: In a prospective superiority trial, eligible patients underwent ERCP at 12 endoscopic units in Japan, from March 2015 through May 2018. Patients were randomly assigned to groups given diclofenac suppositories (50 mg) within 15 minutes after the endoscopic procedure alone (diclofenac-alone group, n = 442) or in combination with sublingual isosorbide dinitrate (5 mg) 5 minutes before the endoscopic procedure (combination group, n = 444). The primary endpoint was the occurrence of PEP. RESULTS: PEP developed in 25 patients in the combination group (5.6%), and in 42 patients in the diclofenac-alone group (9.5%) (relative risk 0.59; 95% confidence interval 0.37-0.95; P = .03). Moderate to severe pancreatitis developed in 4 patients (0.9%) in the combination group, and 10 patients (2.3%) in the diclofenac-alone group (relative risk 0.12; 95% confidence interval 0.13-1.26; P = .12). There was no serious adverse event related to the additional administration of sublingual nitrate. CONCLUSIONS: In a randomized controlled trial, we found that prophylaxis with rectal diclofenac and sublingual nitrate significantly reduces the overall incidence of PEP compared with diclofenac suppository alone. ClinicalTrials.gov, no: UMIN 000016274.

Comparison of anticoagulants and risk factors for bleeding following endoscopic sphincterotomy among anticoagulant users: Results from a large multicenter retrospective study.

BACKGROUND AND AIM: Bleeding is an inevitable and often severe complication after endoscopic sphincterotomy (EST). We aimed to investigate the factors associated with post-EST bleeding in patients treated with anticoagulants. METHODS: The data of patients who underwent EST at 15 hospitals between July 2015 and June 2017 were extracted. We investigated the incidence of post-EST bleeding and risk factors for bleeding in patients treated with anticoagulants. RESULTS: One hundred forty-nine patients undergoing EST who met the inclusion criteria were included in this study. The total-EST bleeding (bleeding occurring during or after EST) rate did not differ between the heparin replacement (8.0%, 6/75) and continuation (16.6%, 2/12; P = 0.37) groups of warfarin users. The total-EST-bleeding rate in the heparin replacement group (12.9%, 4/31) was significantly higher than that in the continuation group (0%, 0/31; P = 0.016) in direct oral anticoagulant (DOAC) users. The rate of total-EST bleeding with continuation of DOAC (0%, 0/31) was significantly lower with continuation of warfarin (16.6%, 2/12; P = 0.021). During-EST bleeding (bleeding occurring during EST) (P = 0.0083) and precut (P = 0.033) were significant risk factors for post-EST bleeding in all 149 patients. Heparin replacement was only a significant risk factor for total-EST bleeding (P = 0.033) in DOAC users. CONCLUSION: Heparin replacement was a significant risk factor for post-EST bleeding in DOAC users; however, there was no significant difference between the bleeding rate of heparin replacement and that of continuation groups in patients taking warfarin. During EST and precut were significant risk factors for post-EST bleeding in all patients treated with anticoagulants.

Efficacy and safety of scheduled early endoscopic ultrasonography-guided ethanol reinjection for patients with pancreatic neuroendocrine tumors: Prospective pilot study.

Endoscopic ultrasonography (EUS)-guided ethanol injection was recently proposed for treatment of patients with small pancreatic neuroendocrine tumors (p-NET); however, tips on how to carry out safe and effective procedures are unclear. We launched a pilot study for scheduled early EUS-guided ethanol reinjection for small p-NET. Major eligibility criteria were presence of pathologically diagnosed grade (G) 1 or G2, tumor size ≤2 cm and being a poor or rejected candidate for surgery. For the treatment, we used a 25-gauge needle and pure ethanol. Contrast-enhanced computed tomography (CE-CT) was carried out on postoperative day 3, and if enhanced areas of the tumor were still apparent, an additional session was scheduled during the same hospitalization period. Primary endpoint was complete ablation rate at 1 month after treatment, and secondary endpoint was procedure-related adverse events. A total of five patients were treated. Median size of the tumor was 10 (range: 7-14) mm. Of the five patients, three underwent an additional session. Median volume of ethanol injection per session was 0.8 (range: 0.3-1.0) mL, and the total was 1.0 (0.9-1.8) mL. Complete ablation was achieved in four of the five tumors (80%) with no adverse events. During 1 year of follow up, none of the patients reported any procedure-related adverse events, and no recurrence of tumor. Scheduled early EUS-guided ethanol reinjection appears to be safe and effective for treating small p-NET (UMIN number: 000018834).

Impact of Body Mass Index of Japanese Gallbladder Cancer Patients on their Postoperative Outcomes.

　We investigated the relationship between body mass index (BMI) and postoperative outcomes in 450 gallbladder cancer patients in Japan. We collected patient information, including sex, age, underlying disease, BMI, stage, surgery method, postoperative time to discharge, and postoperative Medicare fees, from the Japanese administrative database associated with the Diagnosis Procedure Combination system. We classified patient BMIs as underweight (BMI<18.5 kg/m2), normal (BMI≥18.5 kg/m2 and <25 kg/m2) or overweight/obese (BMI≥25 kg/m2), then investigated the relationship between these categories and two postoperative outcomes: time to discharge and postoperative Medicare fees. The median postoperative time to discharge was 12 days in all patients, and 12 days in each of the three weight groups (p=0.62, n.s.). The median postoperative Medicare fees from surgery until discharge were (USD): all patients, $5,002; underweight, $5,875; normal weight, $4,797; and overweight/obese, $5,179 (p=0.146, n.s.). A multivariate analysis with adjustment for competing risk factors revealed that BMI was not associated with increased risk of longer postoperative time to discharge (normal weight: HR 1.17, p=0.29; overweight/obese: HR 1.17, p=0.37) or higher postoperative Medicare fees (OR 0.99, p=0.86, n.s.). Thus, high BMI was not found to be a factor for poor postoperative outcomes in Japanese patients with gallbladder cancer.

Impact of Body Mass Index on Survival of Pancreatic Cancer Patients in Japan.

The impact of body mass index (BMI) on postoperative survival in Japanese patients with pancreatic cancer is unclear. We examined the relationship between preoperative BMI and the prognosis of Japanese patients who underwent surgery for pancreatic cancer to determine whether BMI affects these patients' prognosis. Of the patients who underwent pancreatectomy between January 2004 and August 2015 at our institution, 246 were pathologically diagnosed with pancreatic tubular adenocarcinoma; the cancer was located in the pancreatic head (n=161) and in the body and tail (n=85). We classified the patients by BMI: underweight (n=22), normal weight (n=190), and overweight/obese (n=34) groups. We retrospectively analyzed medical records for patient characteristics, lesion location, disease stage, postoperative complications, chemotherapy, and prognosis. Lesion location, disease stage, postoperative complications, and chemotherapy were not significantly different among the BMI groups. The median survival times were as follows (days): all patients, 686; underweight, 485; normal weight, 694; and overweight/obese, 839. In a multivariate analysis, after adjusting for competing risk factors, low BMI was associated with an increased risk of death (normal weight: HR 0.58, p=0.038; overweight/obese: HR 0.54, p=0.059). High BMI was not found to be a postoperative factor for poor prognosis in Japanese pancreatic cancer patients.

[A case of primary micropapillary carcinoma of the jejunum].

Micropapillary carcinoma (MPC) has been recently reported as a variant of invasive breast carcinoma. MPC is also known to be an aggressive variant of adenocarcinoma, and it is associated with poor prognosis and a high propensity for lymphovascular invasion and lymph node metastases. MPC of the breast, urinary bladder, and lung has been reported relatively frequently; however, there have been few reports on gastrointestinal MPC. Furthermore, MPC of the small bowel has not been reported yet. Here we report a case of MPC of the jejunum. A female septuagenarian was admitted because of anorexia and weight loss. We established a diagnosis of primary jejunal cancer and resected the duodenum and a part of the jejunum. Histologically, the tumor consisted of adenocarcinoma with moderate to poor differentiation. Among the carcinoma cells, approximately 10% formed small papillary neoplastic cell clusters surrounded by clear spaces, suggesting a diagnosis of MPC. We present the details of the case along with a review of relevant literature.

The efficacy and safety of single-session endoscopic ultrasound-guided fine needle aspiration and endoscopic retrograde cholangiopancreatography for evaluation of pancreatic masses.

BACKGROUND/AIMS: There have been limited studies evaluating single-session EUS-FNA and ERCP for evaluation of pancreatic masses. The aim of this study was to determine the safety of single-session EUS-FNA and ERCP, and to compare the diagnostic accuracies of cytodiagnosis by EUS-FNA, ERCP, and their combination. METHODOLOGY: A total of 100 patients with pancreatic masses were prospectively enrolled. All patients underwent single-session EUS-FNA and ERCP. The main outcome measurement was frequency of post-procedural complications. Another measurement was diagnostic accuracy of cytodiagnosis by EUS-FNA, ERCP, and their combination. RESULTS: Procedure-related pancreatitis occurred in 10 patients, but all patients were conservatively managed. Cytodiagnosis by EUS-FNA was significantly superior to ERCP in accuracy. In patients with a pancreatic head mass, 3 cases of false negative EUS-FNA were positive on ERCP. The combination procedures improved accuracy compared with EUS-FNA alone. By contrast, in the subgroup of the pancreatic body or tail mass, the combination of EUS-FNA and ERCP did not improve cytodiagnosis compared to that with EUS-FNA alone. CONCLUSIONS: Single-session EUS-FNA and ERCP appears to be as safe as performing each procedure separately. EUS-FNA should be considered the principal procedure for cytodiagnosis. ERCP has only a complementary role in patients with pancreatic head mass.

[An adult case of intussusception due to inverted Meckel's diverticulum observed by colonoscopy].

A man in his twenties had intermittent abdominal pain in the right lower quadrant for more than 4 years. The abdominal pain persisted after a meal, and he visited our hospital emergency department. We performed an emergency colonoscopy and found a 3-cm mobile polypoid lesion located on the antimesenteric side of the ileum 40 cm from the ileocecal valve and was 85×26×23 mm in size. On the basis of characteristic ultrasound and contrast-enhanced CT findings, our preoperative diagnosis was intussusception due to Meckel's diverticulum translation and performed a laparoscopic ileocecal resection. The pathological diagnosis was Meckel's diverticulum translation with ectopic pancreatic and gastric tissue. Furthermore, we aggregated the cases of adult intussusception due to Meckel's diverticulum translation reported in Japan, and investigated preoperative diagnoses and treatment plans.

Dilatation by Soehendra stent retriever is feasible and effective in multiple deployment of metallic stents to malignant hilar biliary strictures.

BACKGROUND/AIMS: The endoscopic management of malignant hilar biliary strictures using multiple metallic stents (MS) is technically demanding, in the initial deployment of MS and the recovery from MS occlusion with deployment of multiple plastic stents (PS). We evaluated the outcomes of the application of a Soehendra stent retriever (SSR) as a dilator of intractable strictures. METHODOLOGY: Fifty-nine patients with malignant hilar biliary strictures had multiple MS inserted using a partial stent-in-stent procedure. When we encountered intractable strictures, we adopted SSR to dilate the stricture and the interstice of the MS. We evaluated the success rate of MS or PS deployment after SSR application and procedural complications. RESULTS: Five of 59 patients (8%) were subjected to SSR application for the initial MS deployment. MS were successfully deployed in all of these patients (100%). MS occlusion was noted in 27 patients. We applied SSR to seven patients (26%) for the deployment of multiple PS after MS occlusion. In five patients (71%), successful PS deployment was achieved after the SSR application. No complications related to dilatation using SSR occurred in any patient. CONCLUSIONS: SSR proved to be a potent dilator of difficult strictures in the management of malignant hilar biliary strictures.

Management of occluded metallic stents in malignant hilar biliary stricture.

BACKGROUND/AIMS: Little is known about the management of occluded multiple metallic stent (MS) deployed in malignant hilar biliary strictures (HBS). The purpose of this study was to evaluate the endoscopic management of occluded multiple MSs deployed in HBS. METHODOLOGY: Fifty-five patients with unresectable biliary tract carcinoma had multiple MSs inserted due to HBS. The endoscopic intervention through the duodenal papilla was performed on 30 cases that had MS occlusion. The procedure success rate, the survival time after the procedure and the number of endoscopic interventions before death were analyzed, retrospectively. RESULTS: The causes of MS obstruction were tissue ingrowth (n=20), sludge (n=7), tumor overgrowth (n=2), and hemobilia (n=1). Endoscopic cleaning or deployment of plastic stents or metallic stents was performed on these patients and was successfully accomplished only via the transpapillary approach. The survival time after MS obstruction was 219 days. The median number of endoscopic interventions before death was 3. The median interval of endoscopic intervention after the first plastic stent occlusion was 84 days. CONCLUSIONS: Our long-term data regarding the endoscopic management of occluded MSs deployed in malignant hilar biliary strictures are acceptable although the patency time of plastic stents deployed after MS occlusion was relatively short.

Monitoring of CA19-9 and SPan-1 can facilitate the earlier confirmation of progressing pancreatic cancer during chemotherapy.

BACKGROUND: Measurement of objective response to chemotherapy using imaging modalities is sometimes difficult in pancreatic cancer (PC). We aimed to verify whether monitoring of serum tumor markers (TMs), namely carcinoembryonic antigen, CA19-9, DUPAN-2, SPan-1, can facilitate earlier confirmation of treatment failure. METHODS: Monitoring of serum TMs and computed tomography were performed every 4 weeks until progression of disease in 90 patients with PC undergoing gemcitabine therapy. In Group A (January 2006-October 2007), we analyzed the fluctuation rates of TMs with high pretreatment positive rates, and defined the criteria of progressive disease under TM monitoring (TM-PD). In Group B (November 2007-October 2008), we calculated the time to progression (TTP) under this TM-PD criteria, which was compared with the TTP under the RECIST criteria. RESULTS: CA19-9 and SPan-1 had the highest pretreatment positive rates: 83% and 90%, respectively. In Group A (CA19-9, n = 38; SPan-1, n = 36), TM-PD criteria were defined as follows: fluctuation rates were ≥25% for a month or ≥10% for 2 consecutive months in CA19-9, and ≥10% for a month in SPan-1. In Group B (CA19-9, n = 18; SPan-1, n = 17), under these criteria, one-month earlier confirmation of treatment failure was feasible in 61% by CA19-9 and 59% by SPan-1. Furthermore, the combination could facilitate this determination in 72% (35/49), significantly better than CA19-9 alone (P = 0.004). CONCLUSION: Monitoring of serum CA19-9 and SPan-1 is helpful for earlier confirmation of treatment failure during gemcitabine therapy in PC.

Pancreatic Colloid Carcinoma Presenting with Acute Pancreatitis.

Pancreatic colloid carcinoma, also known as mucinous non-cystic carcinoma, is a rare subtype of pancreatic cancer accounting for 1-3% of the pancreatic malignant neoplasms. We herein report a woman who initially presented for acute pancreatitis. Computed tomography showed pancreatic swelling due to acute pancreatitis and a 16-mm mass with an enhanced margin in the pancreatic tail. We performed endoscopic ultrasound fine-needle aspiration. The patient was diagnosed with pancreatic colloid carcinoma, and distal pancreatectomy was performed. This case indicates that pancreatic colloid carcinoma should be considered as a differential diagnosis of pancreatic tumor presenting with acute pancreatitis.

Neuroendocrine tumor of the ampulla of Vater showing chronological endoscopic changes.

We report a rare case of neuroendocrine tumor of the ampulla of Vater in a 53-year-old Japanese male. The patient was admitted to our institution for workup of presyncope secondary to anemia. Medical history was pertinent for coronary artery disease, for which he had drug eluting stents (DES) placed and was on aspirin and clopidogrel therapy. Upper endoscopic evaluation revealed bleeding from an erosion at the ampulla of Vater. Endoscopic therapy with epinephrine and thrombin injection allowed for successful hemostasis and repeat endoscopy 6 months later did not show any changes in lesion character. Repeat endoscopy at 1 year, however, revealed erythema and further erosion on the ampulla of Vater as the lesion had progressed. The patient was diagnosed with carcinoma of the ampulla of Vater. Abdominal computed tomography showed a 9-mm hypervascular tumor at the ampulla of Vater and the patient underwent open pancreatoduodenectomy and lymphadenectomy. Histologically, the tumor consisted of small-sized round cell proliferations with a solid nest pattern. Immunostaining results indicated that the tumor cells were positive for synaptophysin and 2.5% were positive for Ki-67. The final diagnosis was sporadic non-functional neuroendocrine tumor (NET) G1 of the ampulla of Vater. This case demonstrates that NET of the ampulla of Vater, while rare, can have significant changes and growth over time and highlights the importance of follow-up endoscopic evaluations.

Efficacy of intraductal placement of nonflared fully-covered metal stent for refractory perihilar benign biliary strictures: A multicenter prospective study with long-term observation.

BACKGROUND: Endoscopic fully-covered self-expandable metal stents (FCSEMSs) are used to treat benign biliary strictures (BBSs); however, treatment for perihilar BBSs is technically challenging. The aim of this study was to evaluate the usefulness of an unflared FCSEMS designed for intraductal placement in patients with refractory perihilar BBS. METHODS: Twenty-two consecutive patients with perihilar BBS unresolved by endoscopic plastic stent placement at 13 tertiary medical centers were prospectively enrolled. The FCSEMS was placed above the papilla and removed after 4 months. The primary outcome was stricture resolution at 4 months, and the secondary outcomes were technical success, stent removal, adverse events, and recurrence. RESULTS: The technical success rate of intraductal FCSEMS placement was 100%, and plastic stent placement at contralateral or side branch was performed in 86% of patients. The rate of successful stent removal at 4 months was 100%, and stricture resolution was observed in 91% of patients. Stent migration or stent-induced de novo stricture did not occur in any patient. The stricture recurrence rate was 16%, and the median (interquartile range) follow-up duration was 2.8 (1.6-3.3) years. CONCLUSIONS: Intraductal placement of unflared FCSEMS is effective treatment for refractory perihilar BBS.

Correlation between hospital-onset and community-onset Clostridioides difficile infection incidence: Ward-level analysis following hospital relocation.

BACKGROUND: The development of hospital-onset Clostridioides difficile infection (HO-CDI) is affected by patient and environmental risk factors. We investigated changes in the incidence of HO-CDI after relocation to a newly built hospital with 50% private rooms and evaluated the associated factors. METHODS: A retrospective study was conducted to assess trends in CDI incidences before and after the relocation using segmented regression analysis model. The association between CDI incidence and environmental factors at the ward-level was assessed using a linear regression analyses model. RESULTS: The HO-CDI incidence decreased from 6.14 to 1.17 per 10,000 patient-days in the old and new hospital, respectively. Similarly, the community-onset CDI (CO-CDI) incidence decreased from 1.71 to 0.46 per 1000 admissions. HO-CDI incidence was positively correlated with CO-CDI incidence and inversely correlated with the private room ratio (adjusted R2 = 0.83). Almost half of the CO-CDI patients had been hospitalized within 28 days preceding the onset. DISCUSSION: Environmental improvements after relocation may have reduced the reservoir of C. difficile, resulting in a decrease in the number of asymptomatic carriers and CO-CDI patients. CONCLUSION: Relocation to a new hospital significantly reduced HO-CDI incidence, concomitantly decreasing the incidence of CO-CDI, potentially due to environmental improvements.

Bilateral verses bilateral with tri-segmental endoscopic drainage using metal stents for high-grade malignant hilar biliary obstructions: A multicenter, randomized controlled trial: BRAVE study (BRAVE study).

INTRODUCTION: Bilateral endoscopic drainage with self-expanding metallic stent (SEMS) can be used to manage hilar malignant biliary obstruction (HMBO) more effectively in comparison to unilateral drainage. An increased drainage area is predicted to prolong stent patency and patient survival. However, few reports have described the utility of trisegmental drainage and the benefits of using trisegmental drainage remain unknown. Thus, we launched a randomized clinical trial (RCT) to compare the clinical outcomes between bilateral and trisegmental drainage using SEMSs in patients with high-grade HMBO. METHODS AND ANALYSIS: This study was conducted as a multicenter randomized control trial (RCT) in 8 high-volume medical centers in Japan, and will prove the non-inferiority of bilateral drainage to trisegmental drainage. Patients with unresectable HMBO with Bismuth type IIIa or IV who pass the inclusion and exclusion criteria will be randomized to receive bilateral or trisegmental drainage at a 1:1 ratio. At each center, the on-site study investigators will obtain informed consent from the candidates, and will use an electronic data capture system (REDCap) to input necessary information, and register candidates with the registration secretariat. The primary endpoint is the rate of non-recurrent biliary obstruction (RBO) at 180 days after SEMSs placement. A -10% non-inferiority margin is assumed in the statistical analysis of the primary endpoint. Secondary endpoints include the rate of technical and clinical success, time to recurrent biliary obstruction (TRBO), causes of RBO, procedure-related adverse events (AEs), procedure time, TRBO with or without endoscopic sphincterotomy, overall survival, and the technical and clinical success rates at reintervention. DISCUSSION: If the non-inferiority of bilateral drainage is demonstrated, it is predicted that the procedure time will be shortened and the medical cost will be reduced, which will be beneficial to the patient and the medical economy. TRIAL REGISTRATION: Registered in Japan Registry of Clinical Trial-Registration (trial number. jRCTs062220038). This version number 1. Protocol dated Jun 23, 2022.

A 4-week versus a 3-week schedule of gemcitabine monotherapy for advanced pancreatic cancer: a randomized phase II study to evaluate toxicity and dose intensity.

BACKGROUND: This randomized phase II study compared the efficacy and toxicity between 4-week and 3-week schedules of gemcitabine monotherapy in advanced pancreatic cancer. METHODS: Patients with advanced pancreatic cancer were randomly assigned to either a 4-week schedule (gemcitabine at 1000 mg/m² as a 30-min infusion weekly for 3 consecutive weeks every 4 weeks) or a 3-week schedule (gemcitabine at 1000 mg/m² as a 30-min infusion weekly for 2 consecutive weeks every 3 weeks). The primary endpoint was the compliance rate during the first 8 weeks between the two groups. RESULTS: A total of 90 patients were enrolled. The compliance rate during the first 8 weeks was the same (53.3%). For the 4- and 3-week schedules, the tumor response rates were 14.2 and 17.1% (p = 0.92), median progression free survival was 112 and 114 days (p = 0.82), and median overall survival was 206 and 250 days (p = 0.84), respectively. Grade 3-4 neutropenia was the major adverse event in both schedules: 37.7 and 35.5% (p = 0.82). In contrast, thrombocytopenia (platelet count <70000/mm³) was significantly higher for the 4-week schedule: 26.6 and 4.4% (p = 0.008). The mean received dose intensity was equal: 588 and 550 mg/m²/week (p = 0.14). CONCLUSIONS: The 3-week schedule of gemcitabine did not improve the compliance rate during 8 weeks compared with the 4-week schedule, but it attained a comparable efficacy with lower toxicity. Further investigation will be needed to introduce it into daily practice. CLINICAL TRIAL REGISTRATION NUMBER: UMIN ID 974.

Extracellular vesicle-shuttled miRNAs as a diagnostic and prognostic biomarker and their potential roles in gallbladder cancer patients.

Circulating microRNAs (miRNAs) in serum extracellular vesicles (EVs) are a promising biomarker in cancer. We aimed to elucidate the serum EVs miRNA biomarkers to identify patients with gallbladder cancer (GBC) and to clarify their potential roles. One hundred nineteen serum EVs from GBC and non-GBC individuals were isolated by pure-EVs-yieldable size-exclusion chromatography, and then were analyzed using a comprehensive miRNAs array and RT-qPCR-based validation. The functional roles of the identified miRNAs were also investigated using GBC cell lines. Serum EVs miR-1246 and miR-451a were significantly upregulated and downregulated, respectively in GBC patients (P = 0.005 and P = 0.001), in line with their expression levels in cancer tissue according to an in silico analysis. The combination of CEA and CA19-9 with miR-1246 showed the highest diagnostic power (AUC, 0.816; Sensitivity, 72.0%; Specificity, 90.8%), and miR-1246 was an independent prognostic marker of GBC (Hazard ratio, 3.05; P = 0.017) according to a Cox proportional hazards model. In vitro, miR-1246 promoted cell proliferation and invasion, while miR-451a inhibited cell proliferation and induced apoptosis with the targeting of MIF, PSMB8 and CDKN2D. Taken together, miR-1246 in serum EVs has potential application as a diagnostic and prognostic marker and miR-451a may be a novel therapeutic target in GBC.